Project Summary/Abstract: Traumatic brain injury (TBI) is one the leading causes of mortality and morbidity affecting humanity, and a recognized risk factor for late-life neurodegenerative disorders. The absence of validated biomarkers in the neurotrauma field is a barrier to drug development in this area, and as a consequence there are currently no disease-modifying therapies that limit the burden of TBI. TBI is a complex disease process, and there is a need to identify and measure subtypes of injury, in order to develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies. Traumatic axonal injury (TAI) is a common pathologic consequence of TBI, and underlies some of the most disabling consequences of injury, including cognitive and affective problems. Recent breakthroughs in pre-clinical models indicate that novel therapeutic interventions are effective in promoting resilience of injured axons and improving neurologic outcome after experimental TBI. Translation of such promising therapies into successful clinical trials will require prognostic biomarkers that can measure TAI in individual patients, so they can be selected for early phase studies of axono-protective therapies, as well pharmacodynamic biomarkers than can measure the biologic efficacy of such treatments. Currently, the best biomarker for TAI is fractional anisotropy (FA) and mean diffusivity (MD) of white matter tracts, measured using diffusion tensor imaging (DTI) MRI. This technique, while robust, is poorly suited for dynamic longitudinal assessments, and measures the end-result of axonal degeneration, rather than an early step in the neurodegenerative process. Recently, the ability to assay axonal proteins in peripheral blood has made it potentially feasible to assess of TAI rapidly, inexpensively, and longitudinally. The axonal protein that holds the most promise as a marker of axonal degeneration is neurofilament light chain (NF-L). We hypothesize that NF-L is a prognostic biomarker of TAI. Our project has 3 specific aims: Specific aim 1. We will determine reference intervals (RIs) for NF-L according to Clinical Laboratory Standards Institute (CLSI) guidelines, using commercially available assays (Quanterix, LLC, Lexington, MA). Specific aim 2. We will measure NF-L in existing serum samples from participants enrolled in a multi-center observational study (TRACK-TBI) who also have MRIs at 2 weeks and 6 months after injury. The relationship between NF-L elevations and neuroimaging measures of TAI (DTI measure of FA at the 2-week scan) and axonal degeneration (white matter volume at 6 months after injury) will be assessed. Specific aim 3. We will extend the follow-up period of a subset of TRACK-TBI participants from 1 year to 5 years after injury, to assess the relationship between persistent NF-L elevations and neurodegeneration. The existing clinical, imaging, and biomarker data in these subjects will be leveraged to identify risk factors, co- morbidities, and prognostic biomarkers of long-term TBI-associated degeneration.